Staphylococcus aureus, the causative agent of recurrent skin and soft tissue infections, is the most frequent cause of infectious disease morbidity and mortality in the United States. Methicillin-resistant S. aureus strains are associated with failure of antibiotic therapy, a public health crisis that must be addressed by developing new preventive strategies. S. aureus infection does not establish protective immunity, however the key mechanisms of immune evasion for this pathogen were previously not known. We show here that the immunoglobulin Fc-gamma and Fab binding attributes of staphylococcal protein A (SpA) allow S. aureus to escape immune surveillance by blocking the development of protective antibody responses. S. aureus variants that display mutant protein A (SpA/KKAA) are unable to bind Ig Fc-gamma and Fab. These variants allow infected mice to generate protective antibodies and trigger opsonophagocytic killing (OPK) of S. aureus. Protective immunity can be achieved by both active immunization with SpA/KKAA vaccine and by passive transfer of SpA-neutralizing antibodies [SpA/KKAA mouse monoclonal antibodies (mAbs)]. To advance SpA/KKAA-mAbs for clinical development, we generated humanized IgG1, for example SpA/KKAA-huAb 3F6 from SpA/KKAA -mAb 3F6 VH template. huAb-3F6 and mAb-3F6 promote OPK and protection against S. aureus in a host specific manner, suggesting that protective immune responses involve the effector functions of specific FcR receptors on myeloid cells. By characterizing mouse and human FcR receptors responsible for antibody mediated protection, we propose to unravel the molecular and cellular bases of protective immunity against S. aureus. SpA/KKAA -mAbs neutralize both SpA and Sbi, a secreted protein of S. aureus whose Ig binding attributes trigger futile consumption of complement. The contributions of SpA/KKAA and Sbi/KKAA towards the establishment of natural and vaccine induced protective immune responses in mice and guinea pigs will be studied. The guinea pig model offers B cell as well as IgG and IgM antibody repertoires with close resemblance to humans. Generated data will enable rational clinical development of vaccines and immune therapeutics against S. aureus.